The goal of this research is to develop stereocontrolled routes to the antitumor agents blepharocalyxin E and D. Isolated from Alpinia blepharocalyx, these natural products have shown particular promise as potential drug candidates for the treatment of human tumors. Blepharocalyxin D showed the strongest activity against murine colon 26-L5 carcinoma cells in vitro, with an ED50 of 3.61 mu M. Even more significant, blepharocalyxin E displayed inhibitory activity towards human fibrosarcoma HT-1080 cells with an ED50 of 9.02 mu M, which is comparable in activity to the clinically used 5-fluorouracil (ED50 of 8.00 mu M). In order to exploit the full potential of these novel blepharocalyxin arrays as agents for the treatment of human tumors, synthetic studies are planned. The absolute structures of these analogues were assigned based on a variety of spectroscopic data, and also by comparison with previous isolates of A. blepharocalyx. However, a validation of these structure assignments through total synthesis has not been reported. This research, then, is important for two main reasons. In addition to confirming the absolute structures of these natural products, large-scale routes to these compounds would hopefully provide useful analogues for screening. The main body of this proposal will focus on the stereoselective synthesis of cis-fused dioxabicyclic lactones (6,6- and 6,5-fused) and their subsequent use, through ring opening substitution reactions, in the stereocontrolled construction of C-aryl pyranosides. The purpose of this exercise will be to develop useful models for the synthesis of blepharocalyxins D and E. For the synthesis of the 6,5-fused systems, Mn(lll) acetate mediated radical additions of potassium methyl malonate esters to dihydropyrans will be investigated, while a hetero-Diels-Alder route will used to prepare the corresponding 6,6-fused systems. The in situ generation of oxocarbenium ions from both bicyclic lactone series will be studied for the first time. A postulate to be tested is whether electron-rich aromatic donors consistently add to these oxocarbenium ion intermediates with beta-selectivity.